Heparin is an anticoagulant, anti-inflammatory and bacteriostatic polysaccharide, that can be isolated from mammalian tissue, synthetically modified or purified, and/or synthesized artificially. It has a very specific distribution in mammalian tissue; being present only in the basophilic granules of mast cells. Since its discovery in 1916 by the American scientist McLean, heparin has been recognized for its ability to prevent blood from clotting, and for its relatively short half-life in the body. Systemic heparin, administered by injection of the free drug, has been used clinically for more than 50 years as a safe and effective blood anticoagulant and antithrombotic agent. The effects of heparin on blood coagulation/clotting diminish fairly quickly after administration is halted, making its use during surgery and other procedures effective and safe. That is, heparin's anticoagulant and antithrombogenic properties are useful during many medical procedures, for example to minimize undesirable interactions between blood and the man-made surfaces of extracorporeal circuits. Once the procedure is over, the administration of heparin may be then terminated. The heparin concentration in the patient's blood diminishes to a safe level within a few hours. This is particularly important following surgery when healing depends on the ability of blood to clot at the surgical site to avoid bleeding complications. In addition to its well established and continuing use in the treatment of thromboembolic disorders and the prevention of surface-induced thrombogenesis, heparin has more recently been found to have a wide range of other functions apparently unrelated to its function as an anticoagulant. For example, a large number of proteins in blood are now known to bind with high affinity, to free/soluble heparin and/or the closely-related polysaccharide heparan sulfate which is also found in animal tissue, including the luminal surface of healthy blood vessels. Examples are antithrombin (AT), fibronectin, vitronectin, growth factors (e.g. the fibroblast growth factors, the insulin like growth factors, etc.). Human serum albumin (HSA) also binds, but with a lower affinity despite its high concentration in blood.
Infection remains a leading cause of death for battle trauma patients. Due to the nature of the wounds suffered by wounded warriors, 35% of battle trauma patients acquire infections, as opposed to a 9-13% infection rate in civilian trauma patients. Infected patients are at risk of sepsis, in which the patient's immune system over reacts and a “cytokine storm” occurs, where cytokines are released from inflammatory cells in toxic concentrations. The body's own defense system begins to attack healthy tissue, often leading to multiple organ failure and death. Although antibiotics are generally effective in treating an infection, there are very few treatments that attempt to reduce the inflammation caused during sepsis.
Outside the military, more than 750,000 people in the United States develop severe sepsis every year, a syndrome characterized by an overwhelming systemic response to infection that can rapidly lead to organ failure and ultimately death. Additionally, sepsis may elicit the onset of both abnormal clotting and bleeding leading to disseminated intra-vascular coagulation (DIC). Thirty percent of people with sepsis die from its consequences within the first month; up to 50 percent die within six months. The individuals who are most vulnerable to sepsis are wounded warriors, neonates, children, the elderly, and people whose immune systems are compromised by medical treatment, e.g., for cancer, organ transplantation or immune-suppressing diseases such as AIDS.
After many attempts at a pharmacological treatment, survival rates remained unimproved. New clinical protocols, from the Surviving Sepsis Campaign, have made impressive improvements, largely through prevention, but totally new therapies for infected patients are still needed. A serious limitation is the time required to perform cell cultures for pathogen identification for proper antibiotic selection. However, widespread use of antibiotics has itself created resistant strains, suggesting that a biomimetic device-based therapy may be more effective overall.
Drug-resistant bacterial strains are also a major concern for the military. In a recent study, it was found that 70% of S. aureus (SA) infections of service members deployed in Iraq are identified as Methicillin-Resistant S. aureus (MRSA). As broad-spectrum antibiotics are used more frequently, it is expected that new drug-resistant strains will continue to evolve.
The Dual Challenges of Clotting and Intrinsic Separation from a Complex Fluid
When any conventional foreign material is placed in contact with blood, the intrinsic pathway (contact phase) of the coagulation cascade is initiated. Within the first 200 seconds of contact, protein adsorption occurs on the foreign surface and many reactions between enzymes and proteins take place. The culmination of the coagulation cascade is the cleaving of fibrinogen to produce a fibrin clot responsible for thrombus formation and can ultimately leave to form a circulating blood clot or embolus. Emboli can clog blood vessels, depriving downstream tissue of blood, with often life-threatening consequences. A parallel process is platelet adsorption and activation, also by thrombin, in which the platelets change shape and form platelet aggregates. The interaction of blood and a medical device is complicated further by the simultaneous initiation of the extrinsic pathway of the coagulation cascade when tissue factor is exposed. To counteract both pathways of the coagulation cascade during medical procedures, anticoagulants are administered to decrease the rate of fibrin formation by accelerating the rate of Thrombin deactivation. Unfortunately, uncontrolled bleeding and spontaneous hemorrhage can occur with such procedures and is clearly a risk for wounded warriors. Longer term use of soluble systemic heparin can lead to heparin-induced thrombocytopenia, a chronic condition involving severe platelet depletion. Virtually all, materials used in conventional dialysis, and high-surface-area, nano-porous media separation technologies suffer from clotting risks.
Several dialysis-like therapy (DLT) separation technologies for sepsis treatment have been tested by others with little success. They used either dialysis membranes or high-surface area nano-porous supports similar to chromatography media to capture inflammatory molecules, but not bacteria or other adsorbates too large to enter the nano-scale pores of the adsorption media. Continuous veno-venous hemofiltration and high-volume hemofiltration have shown positive results for septic patients with renal failure, but conclusive evidence for benefit of patients without renal failure is lacking.
Additionally, deleterious effects may occur with these earlier technologies. The disadvantage of current technologies include 1) reliance on slow diffusion kinetics within the media's nano-sized pores 2) indiscriminate capture, 3) lack of pathogen capture, 4) use of artificial materials that ironically increase inflammation and 5) need for systemic anticoagulation. In addition, so-called size exclusion separation is difficult in clinical practice since many of the biomarkers (e.g. kidney-creatinine and liver-bilirubin) used by clinicians to evaluate patient status are removed by the separation process itself. One technology that is showing promise in treating Gram negative sepsis uses surface immobilized polymyxin B to capture endotoxins from blood. However, polymyxin B is cationic and is inherently very thrombogenic. In order to prevent coagulation and emoboli formation systemic anticoagulation is required with its attendant complications.